Diuretics.ppt

Diuretics Dr. Priscilla K. Mante Department of Pharmacology, KNUST. 08/19/24 1 Kidney The main function of the kidney is to maintain the constancy of the ‘interior environment’ by  eliminating waste products  r...

Diuretics Dr. Priscilla K. Mante Department of Pharmacology, KNUST. 08/19/24 1 Kidney The main function of the kidney is to maintain the constancy of the ‘interior environment’ by  eliminating waste products  regulating the volume, electrolyte content and pH of the extracellular fluid 08/19/24 2 Kidney The kidneys receive about a quarter of the cardiac output. They filter (in a 70 kg human) approximately 120 litres per day. This filtrate is similar in composition to plasma, apart from the absence of protein. About 99% of the filtered water, and much of the filtered Na+ is reabsorbed. 1.5 litres is voided as urine per 24 h under normal conditions 08/19/24 3 Kidney 08/19/24 4 Rang et al, 2016  DIURETICS 08/19/24 5 Background Primary effect of diuretics is to increase solute excretion, mainly as NaCl Causes increase in urine volume due to increased osmotic pressure in lumen of renal tubule. Certain disease states may cause blood volume to increase outside of narrowly defined limits  Hypertension  Congestive heart failure  Renal failure Dietary Na restriction often not enough to maintain ECF volume and prevent edema  diuretics needed 08/19/24 6 Background Diuretics act either  on cells of the nephron or  by modifying the content of the filtrate 08/19/24 7 Review of Kidney Structure 08/19/24 8 Types of diuretics 1. Loop diuretics 2. Thiazide diuretics 3. Potassium-sparing diuretics 4. Osmotic diuretics 5. Carbonic anhydrase inhibitors 08/19/24 9 Loop diuretics Mechanisms of Action: No transport systems in descending loop of Henle Ascending loop contains Na+-K+-2Cl- co- transporter from lumen to ascending limb cells Ascending limb has low water permeability Loop diuretic blocks co-transporter  Na+, K+, and Cl- remain in lumen, excreted along with water 08/19/24 10 08/19/24 11  Loop diuretics Absorbed from the gastrointestinal tract, usually given by mouth. May also be given intravenously in urgent situations. Given orally, act within 1 h. Given intravenously, peak effect within 30 min. Duration 3-6 hrs. Strongly bound to plasma protein. Enter tubular lumen via proximal tubular secretion because body treats them as a toxic drug. 08/19/24 12 Loop diuretics Generally cause greater diuresis than thiazides; used when they are insufficient High ceiling diuretics Enhance Ca2+ and Mg2+ excretion Decrease excretion of uric acid. 08/19/24 13 Loop diuretics Cl- but not HCO3- is lost in the urine Plasma concentration of HCO3- increases as plasma volume is reduced A form of metabolic alkalosis therefore referred to as 'contraction alkalosis'. Eg. Furosemide, bumetanide 08/19/24 14 Loop diuretics Unwanted effects Hypovolaemia Hypotension Hypokalaemia Metabolic alkalosis Hyperuricaemia Dose-related hearing loss (high dose) 08/19/24 15  Loop diuretics: Clinical uses Hypertension, in patients with impaired renal function Congestive heart failure (moderate to severe) Acute pulmonary edema Chronic or acute renal failure Nephrotic syndrome Hyperkalemia Chemical intoxication (to increase urine flow) 08/19/24 16 Thiazide Diuretics The thiazide diuretics block Na+–Cl− co- transport in the early part of distal tubule. Sodium, chloride, magnesium, and potassium ion excretion are increased. Ca++ absorption by action of parathyroid hormone (PTH) and calcitriol in the early distal tubule (reduce osteoporosis) Co-administration with loop diuretics has a synergistic effect 08/19/24 17 08/19/24 18 Thiazide Diuretics Effective orally Compete with uric acid for the organic anion transporter Bendroflumethiazide - maximum effect 4-6 h and duration is 8-12 h. Chlortalidone has a longer duration of action (24-48 h). Indapamide, hydrochlorthiazide, metolazone Diuresis tends to be moderate since 90% of the filtered sodium has been reabsorbed from the nephron by the time it reaches the distal segment. 08/19/24 19 Thiazide Diuretics Unwanted effects Erectile dysfunction (reversible) Hypokalaemia Hyponatraemia Hypomagnesaemia. Hyperuricemia Hypochloraemic alkalosis Hyperglycemia 08/19/24 20 Thiazide Diuretics: Clinical uses Hypertension Congestive heart failure (mild) Chronic renal failure (as an adjunct to loop diuretic) 08/19/24 21 Comparison of loop and thiazide diuretics 08/19/24 22 Potassium-sparing diuretics Triamterene and amiloride inhibit active Na + reabsorption in the distal convoluted tubule and collecting duct. Reducing the net driving force for K + secretion. They cause a small increase in Na+ and Cl− excretion, decreasing K+ excretion. Their action is independent of aldosterone. 08/19/24 23 08/19/24 24 Potassium-sparing diuretics Spironolactone is a competitive antagonist of the mineralocorticoid aldosterone. It reduces the aldosterone-mediated Na+–K+ exchange at the late distal convoluted tubule, increasing Na+ loss while decreasing K+ loss. Spironolactone is most effective when circulating aldosterone levels are high. 08/19/24 25 Potassium-sparing diuretics Have most downstream site of action (collecting tubule) Not strong diuretics because action is furthest downstream Often used in combination with thiazide diuretics to restrict K+ loss 08/19/24 26 Potassium-sparing diuretics Spironolactone is well absorbed from the gut.  Plasma half-life is only 10 min  Active metabolite, canrenone, has a plasma half- life of 16 h.  Onset of action is slow, taking several days to develop. Eplerenone has a shorter elimination half-life (4-6 h) than canrenone and has no active metabolites.  It is administered by mouth once daily. 08/19/24 27 Potassium-sparing diuretics Triamterene is well absorbed in the gastrointestinal tract.  Its onset of action is within 2 h  Its duration of action 12-16 h. Amiloride is less well absorbed in GIT  Has a slower onset  Peak action at 6 h  Duration of about 24 h 08/19/24 28 Potassium-sparing diuretics Unwanted effects Hyperkalaemia GIT disorders Gynaecomastia, menstrual disorders and testicular atrophy 08/19/24 29 Potassium-sparing diuretics: Clinical Uses Chronic liver failure Congestive heart failure, when hypokalemia is a problem 08/19/24 30 Osmotic diuretics No interaction with transport systems All activity depends on osmotic pressure exerted in lumen Blocks water reabsorption in proximal tubule, descending loop, collecting duct – freely permeable to water. 08/19/24 31 Osmotic diuretics Osmotic diuretics are filtered at the glomerulus but poorly reabsorbed from the lumen of the nephron. The presence of these unabsorbed solutes in the proximal tubule causes decreased reabsorption of water, resulting in a large volume of urine. There is a small increase in Na+ and Cl− excretion. 08/19/24 32 Osmotic diuretics Mannitol Given intravenously Unwanted effects Transient expansion of the extracellular fluid volume Hyponatraemia. Headache Nausea and vomiting 08/19/24 33 Osmotic diuretics: Clinical Uses Acute renal failure Reduce preoperative intraocular or intracranial pressure 08/19/24 34  Carbonic anhydrase inhibitors Mechanisms of Action: Carbonic anhydrase (CA) catalyzes reaction between CO2 and H2O Reversibly inhibit CA predominantly in the proximal convoluted tubules, causing reduction in H+ available for Na+–H+ exchange. CO2 reabsorption from the glomerular filtrate is suppressed, and Na+HCO3− excretion is increased, resulting in an alkaline urine. 08/19/24 35 08/19/24 36 Carbonic anhydrase inhibitors The resulting metabolic acidosis is due to low plasma HCO3−. High concentrations of CA occur in the ciliary process of the eye and the enzyme is involved in aqueous humor formation. CA inhibitors reduce intraocular pressure in glaucoma by decreasing the production of aqueous humor. 08/19/24 37 Carbonic anhydrase inhibitors: Clinical Uses Cystinuria (increase alkalinity of tubular urine) Glaucoma (decrease ocular pressure) Metabolic alkalosis Eg. Acetazolamide (Diamox) 08/19/24 38